Constitutional CTD

The Connective Tissue Disorder (CTD) service at SDGS has been delivering a comprehensive international service for over 10 years.

We offer expert genetic diagnosis for Osteogenesis Imperfecta (OI), Ehlers Danlos Syndrome (EDS), collagen IV- related small vessel disease, hypophosphatsia and other connective tissue disorders. The CTD service is part of Sheffield Childrens NHS Foundation Trust ‘Centre of Excellence’ and provides genetic diagnosis to the NCG Designated Centres for complex/atypical OI and EDS. We are actively involved in research in these fields, striving to promote and develop this specialist diagnostic service for patients and their families.

Osteogenesis Imperfecta

Osteogenesis Imperfecta (OI) is a bone fragility disorder with variable severity ranging from mild to lethal. Approximately 90% of OI patients have a defect in type I collagen, which is a major component of the organic part of bone. This protein is encoded by two genes, COL1A1 and COL1A2. Mutations in these genes are usually inherited in an autosomal dominant manner. Severe OI is usually the result of a de-novo mutation although familial recurrence due to parental mosaicism is reported. The screening strategy developed by the CTD service will identify the causative mutation in >99% of patients with a type I collagen defect.

Testing of the genes known to be associated with autosomal recessive OI, which have been identified in approximately 5% of OI families, is also available.

Ehlers Danlos Syndrome (EDS)

Ehlers Danlos Syndrome is a heterogeneous group of disorders related to underlying connective tissue defects. There are several types of EDS and the specific diagnosis can be difficult to make in some cases.

The presenting symptoms in 70% of adults with vascular EDS are vascular rupture or dissection and gastrointestinal perforation. The only gene associated with vascular EDS is COL3A1 and more than 99% of affected individuals will have a causative mutation identified by the CTD service screening strategy.

Classical EDS presents with skin hyperextensibility, atrophic scarring and joint hypermobility. The majority of mutations are found in the COL5A1 gene with a minority in COL5A2.

The CTD service also screens the genes for hypermobile EDS (TNXB), kyphoscoliotic EDS (PLOD1), Musculocontractural EDS (CHST14) and EDS with progressive kyphoscoliosis, myopathy, and hearing loss (FKBP14) A correct diagnosis and therefore an appropriate management plan has a significant impact on the quality of life for those affected with EDS and their families.

Collagen IV- related disorder

Mutations in the COL4A1 and COL4A2 genes are associated with a range of overlapping small-vessel brain conditions including familial porencephaly and HANAC syndrome (hereditary angiopathy, nephropathy, aneurysms, and cramps).

Familial Porencephaly is characterised by the presence of fluid-filled cavities in the brain, caused by antenatal and/or perinatal intracranial haemorrhage. The neurological symptoms vary in severity and age of onset. Typically affected individuals present with infantile hemiparesis, seizures, mental retardation, dystonia, stroke and migraine.


Hypophosphatasia is an inherited disorders characterized by defective mineralization of bone and teeth. Clinical presentation is highly variable ranging from stillbirth without bone mineralization to early loss of teeth without skeletal manifestations.

Severe forms of the condition usually follow an autosomal recessive inheritance pattern. Milder forms can be inherited in an autosomal dominant or recessive manner. The condition is due to mutations in the alkaline phosphatase liver-type (ALPL) gene which encodes tissue nonspecific alkaline phosphatase (TNAP).

Pseudoxanthoma Elasticum

Pseudoxanthoma elasticum (PXE) is an inherited multisystem disorder primarily affecting the skin, retina and cardiovascular systems.

Skin becomes lax and inelastic particularly on the neck and axilla, and especially in the flexural areas. Another common observation is the papular skin lesions on the neck known as peau d’orange.

Eye findings include angioid streaks in Bruch’s membrane and there are also cardiovascular problems including angina and myocardial infarction.

The two most common mutations observed in the ABCC6 gene are the c.3421C>T mutation, predicted to result in a p.Arg1141* amino acid substitution and the 16.5kb genomic deletion of exons 23_28. Analysis to identify these common mutations is offered as an initial screen for this condition.

Osteoporosis-pseudoglioma syndrome

LRP5 has been shown to play a crucial role in the regulation of bone mass. Mutations within this gene have now been linked to a variety of bone mass disorders such as; osteosclerosis, endosteal hyperostosis, High bone mass trait, osteopetrosis, idiopathic juvenile osteoporosis and Osteoporosis-pseudoglioma syndrome (OPPG). OPPG is an autosomal recessive disorder, generally characterised by congenital or infancy-onset visual loss and skeletal fragility recognised during childhood. Heterozygous carriers of OPPG have a reduced bone mass density (BMD) compared with age and sex matched controls.

A proportion of patients suffering from exudative vitreoretinopathy have also been shown to have mutations within the LRP5 gene. Differential diagnosis of conditions affecting bone mass can be problematic and there can be considerable overlap in clinical spectrum. Identification of a mutation in the LRP5 gene can assist in the diagnostic process and hence affect the clinical management of an individual.

Tests Available: